Response based analysis (RBA) has been developed for prediction of extreme N-year return period responses and design metocean conditions of offshore structures. For applying the RBA, the behaviour of the offshore system subjected to a long history of metocean conditions needs to be predicted, and then, the probabilistic analysis is applied to estimate its long-term responses. Due to the large number of analysis cases required, the structural simulation is usually performed either by simplifying the structural model or by using computationally efficient tools, such as frequency-domain (FD) analysis. These approaches usually decrease the accuracy of predictions mainly when they are utilized for nonlinear systems. On the other hand, employing time-domain (TD) simulations leads to more accurate results but it is computationally expensive. Application of RBA for a weathervaning FPSO, which is the subject of the present study, makes TD analysis an essential requirement because of a highly nonlinear behaviour of the system. In the present study, an efficient methodology is proposed that aims at reducing the computational efforts of RBA by joint application of TD and FD simulations in combining the structural and statistical analyses through a single process, such that the number of time-consuming TD simulations is minimized. After initial screening using the results from FD simulations, the methodology identifies the response events (storms) that contribute the most to the N-year response and sets out an iterative process in which only those events that are most important are analysed by fully-coupled TD simulations. Within such events, a similar approach is also applied to intervals (sea states) where only the most contributing intervals are analysed in TD, and the remaining intervals are left for a less accurate FD analysis without sacrificing the overall accuracy. The proposed methodology provides a robust framework for distinguishing between “mild” and “severe” response events, without specifying any predefined limits for the metocean parameters or making a subjective judgement. Although it is developed for the mooring system of a weathervaning FPSO, it should also be applicable to any type of offshore structure and any structural response. This paper is the first part of the study and concentrates on the development of the efficient methodology to optimize the application of RBA to FPSO mooring systems, whilst its detailed application is subject of the second part of the study.